Extracellular Matrix Signalling and Injury Susceptibility: ACAN and FMOD Variants in Sports-Related Musculoskeletal Injuries.

Background/Objectives: Musculoskeletal soft-tissue injuries are common among physically active individuals and arise from complex interactions between environmental and biological factors. Genetic variation in genes involved in extracellular matrix (ECM) organization may contribute to individual susceptibility to such injuries. This study investigated whether polymorphisms in aggrecan (ACAN, rs2351491 and rs1042631) and fibromodulin (FMOD, rs7543148) genes are associated with susceptibility to sports-related injuries. Methods: The study included 335 physically active Caucasians, comprising 202 participants with a history of non-contact sports-related musculoskeletal injuries and 133 uninjured controls. Genotyping was performed using real-time polymerase chain reaction. Results: No significant associations were observed between the analyzed polymorphisms and overall injury occurrence after correction for multiple comparisons. A nominal association was observed for ACAN rs2351491 in the overall injury comparison under the overdominant model (p = 0.0457), where CT heterozygotes were more frequent among injured participants. The ACAN rs1042631 variant showed nominal associations with anterior cruciate ligament (ACL) injury under the codominant (p = 0.0179), recessive (p = 0.0243), and overdominant (p = 0.0346) models, with the TT genotype associated with lower odds of ACL injury under the recessive model (OR = 0.15, 95% CI: 0.02-1.22). No significant associations were observed for FMOD rs7543148 or for haplotype analysis of ACAN variants. Conclusions: No robust associations were identified between the investigated variants and susceptibility to musculoskeletal soft-tissue injury after correction for multiple testing. Nominal signals observed for ACAN variants, particularly in ACL-focused analyses, warrant further investigation but should be interpreted cautiously and confirmed in larger, independent cohorts.